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Method for preparing (3R, 5S)-3, 5-O-isopropylidene-3, 5, 6-trihydroxy caproic acid hexylic acid derivative

A technology of trihydroxycaproic acid and isopropylidene, applied in the field of preparation-3, can solve the problems of anhydrous operation price, unsuitable for scale-up production, impurity influence reaction, etc., achieves high quality and yield, is convenient for industrialized implementation, The effect of mild reaction conditions

Active Publication Date: 2009-09-23
SICHUAN INDAL INST OF ANTIBIOTICS CHINA NAT PHARMA GROUP CORP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] There are two main problems in the process of the key step compound (2) extending the carbon chain to prepare compound (4): 1) compound (2) is not purified after reacting with carbonyldiimidazole (CDI), causing impurities to affect the subsequent reaction , 2) Magnesium mono-tert-butyl malonate needs multi-step operation to be prepared now, and the preparation process requires anhydrous operation and higher price of magnesium chloride
Based on the above reasons, the original route is not suitable for scale-up production

Method used

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  • Method for preparing (3R, 5S)-3, 5-O-isopropylidene-3, 5, 6-trihydroxy caproic acid hexylic acid derivative
  • Method for preparing (3R, 5S)-3, 5-O-isopropylidene-3, 5, 6-trihydroxy caproic acid hexylic acid derivative
  • Method for preparing (3R, 5S)-3, 5-O-isopropylidene-3, 5, 6-trihydroxy caproic acid hexylic acid derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] 1. Preparation of (S)-2,2-dimethyl-5-oxo-1,3-dioxa-4-acetylimidazole (3):

[0034] 19.5g of compound (2) was dissolved in 150ml of dichloromethane, 18.2g of carbonyldiimidazole (CDI) was added, and after reacting at 25°C for 2h, it was concentrated to obtain 25g of yellow solid; then recrystallized to obtain 21.3g of white flaky solid ( S)-2,2-Dimethyl-5-oxo-1,3-dioxa-4-acetylimidazole (3). mp: 126.9-128.3°C.

[0035] MS: 225(M+1)

[0036] 1 H-NMR (CDCl 3 ): 8.18(s, 1H), 7.48(s, 1H), 7.13(s, 1H), 4.91(m, 1H), 3.28-3.54(dd, 2H), 1.57-1.65(d, 6H)

[0037] 2. (S)-2-(4'-oxo-3', 4'-O-isopropylidene-3', 4'-dihydroxy-1'-hydroxyl-ene)-malonate The preparation of isopropyl ester (4):

[0038] 21.3g of compound (3), 13.6g of Michaelis acid and 6.5g of imidazole were dissolved in 250ml of dichloromethane, stirred at 25°C for 15h, concentrated to obtain 24.2g of crude yellow oil.

[0039] Take part of the crude product column chromatography to obtain light yellow oil (S)-2-(...

Embodiment 2

[0048] 1. Preparation of (S)-2,2-dimethyl-5-oxo-1,3-dioxa-4-acetylimidazole (3):

[0049] Dissolve 20g of compound (2) in 200ml of acetonitrile, add 18.6g of carbonyldiimidazole (CDI), react at 70°C for 1 hour, concentrate to obtain 25g of yellow solid; then recrystallize to obtain 15.4g of white flaky solid (S)- 2,2-Dimethyl-5-oxo-1,3-dioxa-4-acetylimidazole (3). mp: 127-128.3°C.

[0050] MS: 225(M+1)

[0051] 1 H-NMR (CDCl 3 ): 8.18(s, 1H), 7.48(s, 1H), 7.13(s, 1H), 4.91(m, 1H), 3.28-3.54(dd, 2H), 1.57-1.65(d, 6H)

[0052] 2. (S)-2-(4'-oxo-3', 4'-O-isopropylidene-3', 4'-dihydroxy-1'-hydroxyl-ene)-malonate The preparation of isopropyl ester (4):

[0053] 15.4g of compound (3), 19.8g of Michaelis acid and 11.1ml of pyridine were dissolved in 200ml of tetrahydrofuran, stirred at 0°C for 48h, concentrated to obtain 10.3g of crude yellow oil.

[0054] Take part of the crude product column chromatography to obtain light yellow oil (S)-2-(4'-oxo-3',4'-O-isopropylidene-3',4'-di...

Embodiment 3

[0063] 1. Preparation of (S)-2,2-dimethyl-5-oxo-1,3-dioxa-4-acetylimidazole (3):

[0064] Dissolve 20g of compound (2) in 200ml of tetrahydrofuran, add 55.8g of carbonyldiimidazole (CDI), react at 10°C for 5h, concentrate to obtain 28g of yellow solid; then recrystallize to obtain 18g of white flaky solid (S)-2, 2-Dimethyl-5-oxo-1,3-dioxa-4-acetylimidazole (3). mp: 126.5-128.4°C.

[0065] MS: 225(M+1)

[0066] 1 H-NMR (CDCl 3 ): 8.18(s, 1H), 7.48(s, 1H), 7.13(s, 1H), 4.91(m, 1H), 3.28-3.54(dd, 2H), 1.57-1.65(d, 6H)

[0067] 2. (S)-2-(4'-oxo-3', 4'-O-isopropylidene-3', 4'-dihydroxy-1'-hydroxyl-ene)-malonate The preparation of isopropyl ester (4):

[0068] 18g of compound (3), 34.7g of Michaelis acid and 24.3g of triethylamine were dissolved in 250ml of acetonitrile, stirred at 80°C for 1h, concentrated to obtain 7.2g of crude yellow oil.

[0069] Take part of the crude product column chromatography to obtain light yellow oil (S)-2-(4'-oxo-3',4'-O-isopropylidene-3',4'-dih...

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Abstract

The invention discloses a method for preparing (3R, 5S)-3, 5-O-isopropylidene-3, 5, 6-trihydroxy caproic acid hexylic acid derivative, including the following steps: (1) L-malic acid protected hydroxy compound and carbonyl diimidazole (CD I) react in solvent to obtain (S)-2,2- dimethyl-5-oxo-1, 3-dioxa-4-acetyl imidazole; (2) the (S)-2,2- dimethyl-5-oxo-1, 3-dioxa-4-acetyl imidazole and Meldrum's acid react in the solvent under the existence of basic catalyst to prepare (S)-2-(4'-oxo-3', 4'-O-isopropylidene-3', 4'-dihydroxy-1'-hydroxy-alkene)-malonic acid cyclic isopropylidene ester; (3) the (S)-2-(4'-oxo-3',4'-O-isopropylidene-3',4'-dihydroxy-1'-hydroxy-alkene)-malonic acid cyclic isopropylidene ester reacts with methanol to prepare (S)-3, 6-dioxo-5, 6-isopropylidene-5, 6-dihydroxy tert-butyl ester hexanoate; and a target compound can be obtained after further reaction. The method has the advantages of easy acquisition of materials, moderate reaction condition, less material consumption, high product quality and yield and easy implementation of industrialization.

Description

technical field [0001] The invention relates to a method for preparing (3R,5S)-3,5-O-isopropylidene-3,5,6-trihydroxyhexanoic acid derivatives. Background technique [0002] (3R,5S)-3,5-O-isopropylidene-3,5,6-trihydroxyhexanoic acid derivatives are used in the preparation of inhibitors of hypercholesterolemia and hyperlipidemia such as Rui Rosuvastatin, the key intermediate of Pitavastatin. The structural formula is shown in formula (1): [0003] [0004] Where: R stands for hydrogen, saturated -C 1 -C 5 -Alkyl, unsaturated -C 2 -C 5 - Alkyl or benzyl etc. [0005] Among the many methods for preparing the derivative (1), extending the carbon chain is a key step. The current method for extending the carbon chain has the use of tert-butyl lithium acetate as described in US 5,278,313. This reagent must be prepared immediately, and It is necessary to use butyl lithium to operate under anhydrous and low temperature conditions; US 4,983,759 uses expensive tert-butyl bromo...

Claims

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Application Information

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IPC IPC(8): C07D319/06B01J31/02
Inventor 陈宇瑛荣祖元李坤平原于媛媛
Owner SICHUAN INDAL INST OF ANTIBIOTICS CHINA NAT PHARMA GROUP CORP
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